Hotel Mucus: Could synthetic mucus make our gut more inviting to beneficial bacteria?
A recent MIT study suggests that synthetic mucus might help probiotics stay in the gut
Photo provided by Professor Jill Alty
When we eat fermented foods like yogurt or kimchi, we consume probiotics, which are beneficial bacteria that can improve gut health. But before they reach their final destination in the gut, these microbes have to go through the long waterpark slide that is our digestive system, grabbing tightly onto its final part — the intestine — to avoid being flushed out. A recent MIT study takes a step towards understanding how the mucus in our bowels helps such beneficial bacteria stick around and how synthetic mucus could make this process easier.
Staying at “Hotel Mucus”
Most of us are intimately familiar with mucus; it’s that snotty goo from blowing noses or clearing sore throats that helps us get rid of harmful bacteria during infections. But mucus doesn’t just expel pathogens; it’s also capable of holding onto the microbes that are worth keeping in our bodies.
Although mucus might not seem like an inviting place to settle from our perspective, it’s a five-star hotel for probiotic bacteria. In the intestine, it provides food and accommodation in the form of mucins, proteins secreted from cells that line the insides of our body. Mucins have a long protein backbone, like the wire of a bottle brush, with various types of sugars attached like bristles.
When we take probiotic supplements to enhance microbiome diversity, only a small fraction of the microbes in the pills actually reach their destination. And out of the ones that do, most get flushed out within a few days.
To prevent that loss from happening, scientists have been studying how bacteria and mucins interact and whether those interactions can be tweaked to favor beneficial bacteria. This is a challenging task: natural mucins are hard to purify for such studies. Furthermore, the traditional strategy of protein synthesis based on a DNA template cannot fully recreate the natural mucins, as the composition of their sugar bristles cannot be encoded in the template.
In the Kiessling Lab at the MIT Department of Chemistry, then-postdoctoral fellow Dr. Jill Alty took a different approach. Instead of trying to recreate the long protein backbone and the sugary complexity of the mucins in our bodies, Alty and her collaborators made synthetic mucins with simplified polymer backbones. Such molecules act similarly to natural mucins, but are much easier to synthesize at scale. They are also much more customizable: scientists can attach specific sugars one at a time, allowing them to gain finer experimental control and a more detailed understanding of the interactions between mucins and bacteria.
“We make it less complex, more synthetically tractable, and it does the same thing,” said Alty, now an assistant professor with her own lab at Stony Brook University. “You can learn a lot about what’s actually happening at the biological level by simplifying [mucin] to one sugar and a non-natural backbone.”
Making mucus stickier
Alty and her team set out to attach sugars to synthetic polymer backbones and test their interactions with probiotic bacteria. They first picked three bacterial species, all belonging to one of the most dominant classes of probiotics, Lactobacilli, and several types of sugars, attaching them to synthetic backbones one at a time. When they grew the bacteria together with these sugar-coated mucins, they saw that different Lactobacillus species preferred mucins with different sugars attached. Surprisingly, some of the species interacted with a synthetic mucin coated in one type of sugar just as well as they did with a natural mucin coated in a mix of different sugars.
Once the researchers confirmed that the synthetic mucins interact effectively with probiotic bacteria, they wondered whether they could harness these interactions to help bacteria stick to natural gut mucus. To test this, the researchers needed to obtain some natural mucins. The process was not easy; first, Alty’s collaborators in the Ribbeck Lab at the Department of Biological Engineering visited a butcher shop and acquired some pig intestines. Then, they scraped mucus out of those intestines — an activity as gruesome as it sounds — and biochemically purified the relevant mucins through a painstaking procedure that took multiple days.
With natural mucins in hand, the researchers created a pseudo-mucus that resembles the inside of the gut by attaching the purified pig mucins to a plastic plate. To measure how well bacteria stick to natural mucins on their own, Alty added the microbes to this plate and used a machine to shake them for four hours, mimicking the natural disturbances the bacteria might experience in the intestine. In the end, most bacteria were knocked off the mucin-coated plate.
But when Alty added synthetic mucins to the plate covered in pseudo-mucus, a lot more bacteria held on even after vigorous shaking. Not only did synthetic mucins help the microbes cluster together and stick to the plate, but the bacteria actually started to express more digestive enzymes that let them feast on the sugars attached to the synthetic mucins. The researchers found this result promising: it could mean that synthetic mucins both help the bacteria grab on and provide them with food, like a most-welcoming host.
Synthetic mucins as a prebiotic supplement
Alty is excited to further develop synthetic mucins to understand beneficial bacteria’s tastes for mucosal sugars. After all, knowing the guests’ preferences can make our guts more hospitable and hopefully convince the right bacteria to stay at Hotel Mucus.
The endeavor will require nuance. “Initially we had thought [we could] administer the probiotic, which you can buy in a pill … [and] just have the polymer in that same supplement,” Alty recalled. “What we’ve since better understood is that these need to be two separate things. If you feed the bacteria exactly what it wants, it becomes pickier and can’t survive as well in your gut microbiome, so we don’t want to give it its favorite cocktail.”
Although the synthetic mucins are not yet ready to be used as a prebiotic — a food source for probiotic microbes — they have the potential, according to Professor Eric Martens at the University of Michigan Medical School, who does research on the gut microbiome and was not involved in the study.
“They’ve created something synthetic that’s altering the interaction between a bacterium that could be in the gut, like Lactobacillus, and the native mucins that are there above our cells,” Martens said. “It would be very useful if these were somehow specific in a new way for targeting different bacteria that existing prebiotics didn’t use.”
More sugars, more bacteria, and applications beyond the gut
So far, Alty and her collaborators have only tested a few sugars and bacteria, but their approach lends itself well to scaling up this type of exploration without clearing out butcher shops.
“Because the mucins that we secrete are so complex in their carbohydrate patterns, there’s been a lot of hypotheses and speculation about why that complexity exists,” Martens said. The synthetic mucins that Alty and her colleagues developed provide a tractable platform to finally test some of these theories.
There’s also potential in the applications for synthetic mucins beyond the gut. “I think it could be really interesting in the vaginal tract, where you want to recruit certain microbes and exclude others,” Kiessling said. “I love that [research] area, because this has a lot of potential uses for women’s health.”
All the experiments in this study were done in the lab, using plastic plates and temperature-controlled incubators, without competition from other gut-dwelling microbes. Next, Alty would like to test the efficacy of synthetic mucins as prebiotics in animals — in a more realistic and more competitive environment for the bacteria.
Whether synthetic mucins can improve probiotic retention in humans is still an open question, but both Alty and Kiessling are hopeful.
“I love the idea that we could think about providing prebiotics, molecules that bacteria eat, to promote growth of certain bacteria and minimize growth of others,” Kiessling said.